Chapter 66: Aplastic Anemia

Aplastic Anemia (AA)

Aplastic anemia is a distinct entity characterized by peripheral blood cytopenias and bone marrow hypocellularity. Aplastic anemia can be acquired or congenital. Acquired aplastic anemia is distinguished from iatrogenic marrow aplasia, the common occurrence of marrow hypocellularity after intensive cytotoxic chemotherapy

Epidemiology

Incidence: 2 per 1 million of population per year (West) and 2- to 3-fold higher in Asia

Male-to-female ratio: 1:1

Incidence of aplastic anemia. In: Kaufman DW et al., eds. The drug etiology of agranulocytosis and aplastic anemia. New York, NY: Oxford University Press; 1991:159–169

Young NS et al. Blood 2006;108:2509–2519

Disease Severity

Severe aplastic anemia

1. Bone marrow cellularity <25% of normal or 25–50% of normal with <30% residual hematopoietic cells, and

2. Two out of 3 criteria: (a) neutrophils <500/mm³; (b) platelets <20,000/mm³; (c) reticulocytes <1%

Very severe aplastic anemia

1. Bone marrow cellularity <25% of normal or 25–50% of normal with <30% residual hematopoietic cells, and

2. (a) Neutrophil count <200/mm³ and (b) platelets <20,000/mm³ or reticulocytes <1%

Moderate (nonsevere) aplastic anemia

Patients who do not fulfill the above criteria

Bacigalupo A et al. Br J Haematol 1988;70:177–182

Bacigalupo A et al. Semin Hematol 2000;37:69–80

Camitta BM et al. Blood 1976;48:63–70

Rosenfeld S et al. JAMA 2003;289:1130–1135

Young NS et al. Biol Blood Marrow Transplant 2010;16(1 Suppl):S119–S125

Etiology and Classification

1. Acquired aplastic anemia

   1. Idiopathic (2/3 of all cases)

   2. Secondary

      1. Drugs

         1. Predicted:

            • (1) Cytotoxic chemotherapeutic agents

              • Alkylating agents (busulfan, cyclophosphamide, melphalan)

              • Antimitotics (vincristine, vinblastine)

              • Antimetabolites (antifolate compounds, nucleotide analogs)

         2. Idiosyncratic:

            • (1) Chloramphenicol

            • (2) Antiprotozoal agents (quinacrine, chloroquine)

            • (3) Nonsteroidal antiinflammatory drugs: ibuprofen, indomethacin, sulindac, diclofenac, naproxen, phenylbutazone

            • (4) Anticonvulsants: hydantoins, carbamazepine, phenacemide, ethosuximide

            • (5) Gold and arsenic

            • (6) Sulfonamides

            • (7) Antithyroid drugs (methimazole, methylthiouracil, propylthiouracil)

            • (8) Oral hypoglycemic agents (tolbutamide, carbutamide, chlorpropamide)

            • (9) Penicillamine

            • (10) Mesalazine

      2. Chemicals: benzene, insecticides

      3. Radiation

      4. Viral infections:

         1. Parvovirus (rare, usually causes transient aplastic crisis, pure red cell aplasia)

         2. Hepatitis viruses (non-A, non-B, non-C hepatitis)

         3. Epstein-Barr virus

         4. Human immunodeficiency virus

      5. Immune disorders:

         1. Eosinophilic fasciitis

         2. Systemic lupus erythematosus

         3. Graft versus host disease, transfusion associated

         4. Hypoimmunoglobulinemia

         5. Thymoma and thymic carcinoma

      6. Paroxysmal nocturnal hemoglobinuria

      7. Pregnancy

2. Inherited aplastic anemia

   1. Fanconi anemia

   2. Dyskeratosis congenita

   3. Shwachman-Diamond syndrome

   4. Amegakaryocytic thrombocytopenia

Young NS. In: Young NS, ed. Bone Marrow Failure Syndromes. 1st ed. Philadelphia, PA: WB Saunders; 2000:1–46

Work-up

Differential Diagnosis of Pancytopenia

Pancytopenia with hypocellular bone marrow

1. Acquired aplastic anemia

2. Inherited aplastic anemia

3. Myelodysplasia syndromes (rare)

4. Aleukemic leukemia (rare)

5. Lymphomas of bone marrow (rare)

Pancytopenia with cellular bone marrow

Primary bone marrow diseases:

1. Myelodysplasia syndrome

2. Paroxysmal nocturnal hemoglobinuria

3. Myelofibrosis

4. Hairy cell leukemia

5. Myelophthisis

6. Bone marrow lymphoma

Secondary to systemic diseases:

1. Systemic lupus erythematosus

2. Sjögren syndrome

3. Hypersplenism

4. Vitamin B₁₂ deficiency, folate deficiency

5. Alcoholism

6. Brucellosis

7. Ehrlichiosis

8. Sarcoidosis

9. Tuberculosis and atypical mycobacteria

Hypocellular bone marrow with or without cytopenia:

1. Q fever

2. Legionnaires' disease

3. Toxoplasmosis

4. Mycobacteria

5. Tuberculosis

6. Anorexia nervosa, starvation

7. Hypothyroidism

Treatment Options

Hematopoiesis can be restored in severe aplastic anemia with allogeneic hematopoietic cell transplantation (allo-HCT) or immunosupressive therapy. HCT is preferred when feasible as it is curative. However, most patients are not suitable candidates for optimal initial HCT because of lack of a matched sibling donor, lead time to identify a suitable unrelated donor, age, comorbidities, or access to transplantation. Patients <50 years old with severe aplastic anemia who have an HLA-compatible sibling should be offered allo-HCT as first-line treatment. The combination of ATG with cyclosporine is the standard for immunosuppressive therapy and should be considered for nonsevere transfusion-dependent AA patients or patients who lack an HLA-compatible sibling donor. Patients who do not respond at 6 months following ATG with cyclosporine should be considered for matched unrelated-donor HCT (children and young adults) or receive a second course of ATG + cyclosporine if no matched unrelated donor is available

Transplantation for AA from an HLA-identical sibling donor has improved over the years with a 70–80% chance of long-term cure. Graft failure rates following allo-HCT range from 4–14% and the development of chronic graft-versus-host disease range from 30–40% of patients. The correlation of increasing age with the risk of GVHD and the significant morbidity and mortality of this transplant complication continues to impact on the decision to pursue HCT versus immunosupressive therapy as initial therapy in adults with SAA. A report by the Center for International Blood and Marrow Transplant Research of more than 1300 severe aplastic anemia patients who were transplanted from 1991 to 2004, survival at 5 years for patients younger than 20 years of age was 82%, for those 20 to 40 years of age 72%, and for those older than 40 years, closer to 50%. Rates of GVHD increased with age, accounting for much of the decreased survival in older patients and the long-term morbidity. Thus, outcomes in the most favorable age group (children with matched sibling donor) resulted in long-term survival of approximate 80%

In severe aplastic anemia, peripheral blood stem cell results have been inferior to grafts of bone marrow origin. Higher rates of chronic GVHD were observed in patients of all ages undergoing HCT with peripheral blood compared with bone marrow derived stem cell grafts. It is recommended bone marrow stem cells be used rather than granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells

Gupta V et al. Haematologica 2010;95:2119–2125

Kojima S et al. Int J Hematol 2011:93:832–837

Scheinberg P, Young NS. Blood 2012;120:1185–1196

Young NS et al. Biol Blood Marrow Transplant 2010;16(1 Suppl):S119–S125

Regimen: Aplastic Anemia Therapy: Lymphocyte Immune Globulin, Antithymocyte Globulin (Equine) (ATG) + Cyclosporine

Rosenfeld S et al. Blood 1995; 85:3058–3065

Rosenfeld S et al. JAMA 2003;289:1130–1135

Scheinberg P et al. N Engl J Med 2011;365:430–438 + supplementary information available online at: www.nejm.org/doi/full/10.1056/NEJMoa1103975

Premedication:

Diphenhydramine 25–50 mg; administer orally 60 minutes before each antithymocyte globulin treatment

Lymphocyte immune globulin, antithymocyte globulin^✫ (equine) (ATG) 40 mg/kg per day administered through a high-flow (central) vein, vascular shunt, or arteriovenous fistula in a volume of 0.9% sodium chloride injection (0.9% NS), 5% dextrose and 0.2% sodium chloride injection (D5W/0.2% NS), or 5% dextrose and 0.45% sodium chloride injection (D5W/0.45% NS) sufficient to produce a solution with antithymocyte globulin concentration≤4 mg/mL, over at least 4 hours for 4 consecutive days, on days 1–4 (total dosage/course = 160 mg/kg)

Notes:

1. ATGAM (antithymocyte globulin [equine]) product labeling recommends intradermal skin testing prior to administration. Patients with a reactive skin test may still receive antithymocyte globulin after desensitization

2. Always administer antithymocyte globulin through a 0.2- to 1-μm pore size inline filter

3. After dilution, ATG should be allowed to come to room temperature before administration begins

4. The initial infusion rate should be 10% of the total volume per hour. For example, for a total volume of 500 mL, start at a rate of 50 mL/hour for the first 30 minutes. If there are no signs of an adverse reaction, the infusion rate can be advanced to complete the infusion over no less than 4 hours

Prednisone 1 mg/kg per day; administer orally starting prior to the first dose of ATG, and continuing for a total of 10 days; the daily dose is gradually decreased (tapered) over the following 7 days, and then discontinued

Adults:

Cyclosporine (initially) 6 mg/kg per dose; administer orally every 12 hours, continually for 6 months, commencing on day 1. Starting at 6 months, gradually decrease cyclosporine doses over the subsequent 18 months (taper to discontinuation)

Children:

Cyclosporine (initially) 7.5 mg/kg per dose; administer orally every 12 hours, continually for 6 months, commencing on day 1. Starting at 6 months, gradually decrease cyclosporine doses over the subsequent 18 months (taper to discontinuation)

Notes:

1. Cyclosporine doses are adjusted to maintain serum concentrations within the range of 200–400 mcg/L (166–333 nmol/L), and as a factor of renal and hepatic toxicity

2. Prophylaxis for Pneumocystis jirovecii: Pentamidine 300 mg by inhalation every 4 weeks beginning the first month of therapy, and continue for at least 6 months

3. Antibacterial, antiviral, and antifungal prophylaxes are not routinely administered with standard equine ATG and cyclosporine treatment

Patient Population Studied

A total of 120 consecutive patients, 2–77 years of age, were randomly assigned to horse ATG or rabbit ATG (60 patients in each group)

Efficacy

At 3 years, the survival rate was 96% (95% CI, 90–100) in the horse-ATG group as compared with 76% (95% CI, 61–95) in the rabbit-ATG group (P = 0.04) when data were censored at the time of stem-cell transplantation, and 94% (95% CI, 88–100) as compared with 70% (95% CI, 56–86; P = 0.008) in the respective groups when stem-cell–transplantation events were not censored

Disposition among nonresponders at 6 months to immunosuppression:

Among the 17 nonresponders to horse-ATG, 5 underwent stem-cell transplantation, 4 from a histocompatible sibling and 1 from a matched unrelated donor. Eight patients underwent second-line immunosuppression (rabbit-ATG plus cyclosporine or alemtuzumab). Of the 29 nonresponders in the rabbit-ATG group, 23 patients received second-line immunosuppression (horse-ATG plus cyclosporine or alemtuzumab). Four patients underwent stem-cell transplantation, 3 from a histocompatible sibling and 1 from an unrelated donor. Six patients who did not respond to second-line immunosuppression went on to receive a stem-cell transplantation, 1 from a histocompatible sibling, 4 from an unrelated donor, and 1 patient received a haploidentical/umbilical cord transplant

Toxicity

Table Graphic Jump Location

|Download (.pdf)|Print

Toxicity

Adverse Events	Horse ATG	Rabbit ATG
Related to immunosuppression
Serum sickness	2	5
Chest pain	1	0
Hemolysis✫	0	1
SVT	0	1
Azotemia	1	0
PRES	0	1
Hemorrhage
CNS	0	1
Vitreous	0	1
Hematemesis	0	1
Epistaxis	1	1
Menorrhagia	2	0
Hemoptysis	1	0
Infection
Neutropenia and fever, negative cultures	23	16
Neutropenia and fever, positive cultures	17	14
Polymicrobial†	0	6
Pneumonia‡	1	3
Necrotizing fasciitis§	0	1
Clostridium difficile	2	2
Retropharyngeal abscess	0	1
Perirectal abscess	0	1
Periorbital cellulitis	1	0
Tonsillitis/pharyngitis	2	1
Appendicitis/typhlitis	0	4
Otitis media	1	0
Epididymitis	0	1
Upper respiratory infection	5	1
Other	9	11
PRES, Posterior reversible encephalopathy syndrome; SVT, supraventricular tachycardia; CNS, central nervous system Serious adverse events depicted are those that resulted in prolonged hospitalization, hospital admission, or death Events shown are those that occurred after the first cycle of immunosuppression. Repeated hospitalizations in the same subject were counted as separate events ✫Hemolysis occurred after ATG infusion in a patient with a large underlying paroxysmal nocturnal hemoglobinuria clone †Patients with multiple microbial isolates and/or different sites of infection are categorized as having polymicrobial infection. The organisms recovered and sites for each of the patients were: (a) Escherichia coli, Staphylococcus epidermidis, Enterococcus faecium, Acinetobacter baumannii (all in blood); Enterococcus sp., Staphylococcus sp., and mold (left turbinate biopsy); (b) Pseudomonas sp., Klebsiella sp., Staphylococcus epidermidis, Streptococcus viridans, Staphylococcus hemolyticus, Enterococcus faecium, and Stenotrophomonas maltophilia (all in blood); (c) Enterobacter cloacae, Pseudomonas aeruginosa (respiratory cultures); Acinetobacter baumannii, Mycobacterium gordonae, Fusarium sp., Acinetobacter baumannii, Enterococcus faecalis (sinus culture), Corynebacterium sp. (blood), Proteus mirabilis (urine); (d) Propionibacterium acnes, Staphylococcus aureus, Candida albicans (throat); (e) Streptococcus sp. (blood), Trichosporon asahii (sinus), Candida albicans (skin); (f) Enterococcus faecium, Staphylococcus epidermidis (blood), Klebsiella pneumoniae (urine) ‡One case of fungal pneumonia in each group §Caused by Clostridium sp In 3 subjects viral infection was confirmed by nasopharyngeal wash

Clonal evolution:

The cumulative incidence of clonal evolution at 3 years (in all patients, those with and those without a response) was 21% (95% CI, 7–33) in the horse-ATG group and 14% (95% CI, 1–25) in the rabbit-ATG group (P = 0.69). Among patients treated with horse-ATG, 1 each had deletion 3, deletion 5q, deletion 13q, deletion 20q, and leukemia, and 4 had monosomy 7. In 2 patients, monosomy 7 was preceded by t(12;13) and deletion 13q. In the rabbit-ATG group, 5 patients had monosomy 7, and 1 had deletion 13q

Therapy Monitoring

1. During antithymocyte globulin infusion: CBC with differential, LFTs, electrolytes

2. After antithymocyte globulin therapy: CBC monitoring is dependent on blood counts. If they are stable CBC with differential can be as infrequent as once every 2–3 weeks. Patients requiring platelets may need more frequent CBC

3. Six months after the start of therapy: Bone marrow biopsy and aspiration. If patients are stable based on blood counts, bone marrow biopsy may not need to be repeated

Therapeutic Drug Monitoring—Cyclosporine:

1. When initiating cyclosporine treatment and after any dose adjustments, monitor cyclosporine trough concentrations (sampled at the end of a dosing interval) every 4–7 days until stable concentrations are achieved

2. For patients on a stable cyclosporine regimen, monitor trough levels every 2 weeks

3. More frequent cyclosporine monitoring is recommended whenever cyclosporine dosage adjustments are made, serum creatinine increases, and when a patient's concomitantly administered medication regimen is changed (be wary of drugs that potentially perturb cytochrome P450 CYP3A subfamily enzymes expression, availability, or activity)

4. Cyclosporine doses are adjusted to maintain blood concentrations within the range of 200–400 mcg/L (166–333 nmol/L)

Notes

1. Avoid other nephrotoxic drugs concurrent with cyclosporine treatment

2. Granulocyte-colony stimulating factors (G-CSF) should be administered as clinically indicated, usually for evidence of infection such as fever or localized inflammation in the setting of severe inflammation. Emergence of monosomy 7 has been linked to exogenous use of G-CSF

    The role of G-CSF was evaluated in 192 patients with newly diagnosed severe AA not eligible for transplantation who were entered into a multicenter, randomized study to receive ATG/cyclosporine with or without G-CSF. Overall survival (OS) at 6 years was 76% ± 4%, and event-free survival (EFS) was 42% ± 4%. No difference in OS/EFS was seen between patients randomly assigned to receive or not to receive G-CSF, neither for the entire cohort nor in subgroups stratified by age and disease severity. Patients treated with G-CSF had fewer infectious episodes (24%) and hospitalization days (82%) compared with patients who did not receive G-CSF (36%; P = 0.006; 87%; P = 0.0003)

   Tichelli A et al. Blood 2011;117:4434–4441

3. Patients with AA usually receive irradiated blood products during and after ATG treatment. This policy should continue for at least as long as patients are receiving immune suppressive therapy

   Guidelines for administering antithymocyte globulin (ATG):

   • Severity and frequency of toxicities (rigors, fevers, oxygen desaturation, hypotension, nausea, vomiting, anaphylaxis) are greatest during the first day of infusion and diminish with each subsequent day. Toxicities generally subside after completing treatment

   • Adverse effects generally can be managed while continuing antithymocyte globulin infusion

   • Most patients receiving ATG will develop fever. Most fevers are not infectious in origin. Patients with fever and neutropenia should be treated with broad-spectrum antibiotics empirically

   Marsh J et al. Br J Haematol 2010;150:377–379

   Allergy skin testing prior to ATG administration:

   • Advise patients to avoid using H₁-receptor antagonists for 72 hours before skin testing

   • Antithymocyte globulin (equine) is freshly diluted (1:1000) with 0.9% sodium chloride injection (0.9% NS), to a concentration of 5 mcg/0.1 mL, and administered intradermally

   • Administer 0.1 mL 0.9% NS, intradermally in a contralateral extremity as a control

   • Observe every 15–20 minutes during the first hour after intradermal injection

   • A local reaction ≥10 mm with a wheal, erythema, or both, ± pseudopod formation and itching or a marked local swelling, is considered a positive test. For patients who exhibit a positive test result, consider desensitization prior to therapy

   • If antithymocyte globulin is administered after a locally positive skin test, administration should only be attempted in a setting where intensive life support facilities are immediately available and with the attendance of a physician familiar with the treatment of potentially life-threatening allergic reactions

   • Systemic reactions preclude antithymocyte globulin administration; for example, generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis

   Note: The predictive value of skin testing has not been proved clinically; that is, allergic reactions including anaphylaxis have occurred in patients whose skin test result is negative

   Monitoring during ATG administration:

   • Patients should remain under continual surveillance

   • Assess peripheral vascular access sites for thrombophlebitis every 8 hours

   • Monitor vital signs and assess for adverse reactions (flushing, hives, itching, SOB, difficulty breathing, chest tightness) before starting administration, then:

     • During initial dose: Continually during the first 15 minutes, then every 30 minutes × 2, then at least every hour until administration is completed

     • During subsequent doses: 30 minutes after initiating ATG infusion

Infusional Toxicities of Antithymocyte Globulin

Table Graphic Jump Location

|Download (.pdf)|Print

Infusional Toxicities of Antithymocyte Globulin

Adverse Events	Interventions
Rigors	Antihistamines (eg, diphenhydramine 25–50 mg; administer intravenously or orally every 6 hours as needed) Meperidine 12.5–50 mg; administer intravenously every 3–4 hours as needed
Nausea, vomiting	Antiemetic rescue. Give antiemetic prophylaxis during subsequent antithymocyte globulin treatments (secondary prophylaxis)
Anaphylaxis✫	Immediately STOP administration; administer steroids, assist respiration, and provide other resuscitative measures. DO NOT resume treatment
Thrombocytopenia, anemia	Blood product transfusions as needed†
Fever and neutropenia‡	Broad-spectrum antibiotics empirically, if ANC <500/mm3. May give acetaminophen 650 mg orally every 4 hours
Hypotension	Fluid resuscitation
Refractory hypotension	May indicate anaphylaxis. Stop antithymocyte globulin infusion and stabilize blood pressure. Intensive Care Unit support
Oxygen desaturation	Oxygen therapy
Refractory oxygen desaturation	Discontinue antithymocyte globulin. Intensive Care Unit support
Respiratory distress	Discontinue antithymocyte globulin. If distress persists, administer an antihistamine, epinephrine, corticosteroids
Rash, pruritus, urticaria	Administer antihistamines and/or topical steroids for prophylaxis and treatment
Serum sickness-like symptoms§	Administer prophylactic glucocorticoids
Hepatotoxicity	Monitor LFTs
✫Anaphylaxis (<3% of patients) most frequently occurs within the first hour after starting antithymocyte globulin infusion. After the first hour, adverse effects occur as result of a delayed immune response and generally can be managed while continuing the antithymocyte globulin infusion †Concomitant administration of blood products should be avoided with antithymocyte globulin infusions to avoid confusing transfusion reactions with reactions to antithymocyte globulin ‡Most patients who receive antithymocyte globulin will develop fever as a result of the drug. Most fevers are not infectious in origin, but patients should receive broad spectrum antibiotics empirically until an infectious process is ruled out §Type II hypersensitivity reactions/serum sickness consisting of fever, rash, and arthralgia develops in approximately 85% of patients between 7 and 14 days after ATG treatment. These symptoms can be managed with corticosteroids An isolated increase in serum alanine aminotransferase (ALT) frequently has no clinical significance. Generally, liver function abnormalities are transient and return to normal within one month   Bevans MF, Shalabi RA. Clin J Oncol Nurs 2004;8:377–382

Aplastic Anemia Therapy: Androgens

Bacigalupo A et al. Br J Haematol 1993;83:145–151

Besa EC. Semin Hematol 1994;31:134–145

Heimpel H. Acta Haematol 2000;103:11–15

Najean Y. Am J Med 1981;71:543–551

Passweg JR, Marsh JC. Hematology Am Soc Hematol Educ Program 2010:36–42 (review)

Oxymetholone 0.25–5 mg/kg per day; administer orally, continually

Danazol 600–800 mg per day; administer orally, continually

Indications

Androgens were used extensively in the treatment of AA for many decades before the availability of immunosuppressants

Patients with aplastic anemia who are not candidates for HSCT or who did not respond to immunosuppressive therapy

Efficacy

Therapy Monitoring

1. Twice weekly to every 2–3 weeks: CBC monitoring is dependent on blood counts. If they are stable, a CBC with differential can be obtained as infrequently as once every 2–3 weeks. Patients requiring platelets may need more frequent CBCs, but not more than twice weekly and usually only once weekly

2. Monthly: LFTs

3. Periodic: Serum HDL and LDL (anabolic steroids have been reported to lower the level of high-density lipoproteins and raise the level of low-density lipoproteins. These changes usually revert to normal on discontinuation of treatment)

    Serum iron and iron-binding capacity

   • Iron-deficiency anemia has been observed in some patients treated with steroids. If iron deficiency is detected, it should be appropriately treated with supplementary iron

4. Every 6 months: X-ray examinations of bone in prepubertal patients to determine the rate of bone maturation and drug effects on the epiphyseal centers

Notes

1. A trial of androgens for 3–6 months is recommended to evaluate a patient's response

2. Patients may respond to different androgen preparations. An alternative product may be used if the initially chosen androgen was not effective or no longer produces a therapeutic benefit

3. Hypoglycemic drug regimens may need to be adjusted in diabetic patients who receive anabolic steroids

4. Anabolic steroids may suppress clotting factors II, V, VII, and X, and increase prothrombin times

5. Danazol may produce symptoms of benign intracranial hypertension (papilledema, headache, nausea, vomiting, and visual disturbances). Advise patients who exhibit these symptoms to immediately discontinue danazol and refer them to a neurologist for further diagnosis and care

6. Contraindications to the use of androgens include undiagnosed abnormal genital bleeding, impaired hepatic function, impaired renal function, impaired cardiac function, pregnancy, porphyria, breast cancer in women with hypercalcemia, prostate cancer

Toxicity

Common: Acne, seborrhea, edema, emotional lability, nervousness, flushing, sweating, hair loss, hirsutism, menstrual disturbances, vaginal dryness and irritation, voice change, weight gain, changes in libido

Serious side effects: Cholestatic jaundice, peliosis (hemorrhagic liver cysts), hepatic tumors

Peliosis hepatis and hepatic adenomas may be silent until complicated by acute, potentially life-threatening intraabdominal hemorrhage

Hepatotoxicity occurs less frequently with parenteral preparations

Oxymetholone: Decreased serum HDL ± increased LDL. Cholestatic hepatitis and jaundice ± pruritus at low doses; may be associated with acute hepatic enlargement and RUQ pain. Continued therapy has been associated with hepatic coma and death

Danazol: Thromboembolism, thrombotic and thrombophlebitic events, including sagittal sinus thrombosis and life-threatening or fatal strokes; benign intracranial hypertension (pseudotumor cerebri)